Acetaminophen (USAN) or paracetamol (INN) (chemically known as N-(4-hydroxyphenyl)acetamide or N-(4-hydroxyphenyl)ethanamide) is an antipyretic and analgesic commonly used to manage fever of any etiology, minor to severe pains (including post-operative pain) and a variety of aches. Acetaminophen is well tolerated and lacks many of the undesired effects of other analgesics, such as non-steroidal anti-inflammatory drugs (NSAIDs) or types of cyclooxygenase (COX) inhibitors (e.g., stomach lining irritation, adverse effects on platelets and renal function, fetal ductus arterious closure complications, and Reye's syndrome).
Acetaminophen has also been shown to be effective in protecting tissues from ischemic damage (i.e. damage caused by ischemia as well as reperfusion that follows ischemia). For instance, in guinea pigs, acetaminophen was found to decrease apoptosis in myocytes, which were subjected to low-flow global myocardial ischemia for 30 minutes followed by 60 minutes of reperfusion (See Am J Physiol Heart Circ Physiol 293: H3348-H3355, 2007). In another study, acetaminophen was found to inhibit both lipid peroxidation and superoxide anion generation, resulting in retained structural integrity of the rat hippocampus insulted with quinolinic acid in a cerebral ischemia model (See Metabolic Brain Disease 21 (2-3): 180-190, 2006). Following a study with cultured CNS neurons, it was concluded that acetaminophen has anti-oxidant and anti-inflammatory effects on neurons (See J Neuroinflammation 6:10 doi: 10.1186/1742-2094-6-10, 2009). As with its analgesic applications, an important element of the treatment of ischemic or neurological diseases with acetaminophen is the speed at which therapeutic intervention and peak therapeutic blood concentration occurs.
Opioids have gained widespread use in the clinical setting (for example, to control post-operative pain) due to their excellent analgesic properties and onset of action. However, the use of certain opioids is often accompanied by significant adverse side-effects (e.g., respiratory depression, biliary spasm, constipation, sedation, addiction and abuse potential, and post-operative nausea and vomiting, etc.) which make them less desirable. The alternative use of NSAIDs, however, impairs blood clotting (in addition to the side effects previously mentioned), which is highly undesirable in post-operative settings that require active wound healing and blood clotting. Due to the undesirable qualities of certain NSAIDs, COX inhibitors, and opioids, particularly in certain clinical settings, there has been a need to develop effective formulations of acetaminophen and/or alternative therapies to acetaminophen.
However, it is well known that under certain conditions acetaminophen may be toxic to the liver (known as hepatotoxicity). It is estimated that most liver transplants in the United States are caused by acetaminophen toxicity, and 49% of all acute liver failure cases in 2004 were the result of acetaminophen overdose. Each year, overdoses of acetaminophen (sold as Tylenol® and other brands) account for more than 56,000 emergency room visits and an estimated 458 deaths from acute liver failure (Harvard Women's Health Watch, March, 2006). According to a study from the U.S. Acute Liver Failure Study Group (Lee W M. Hepatology 2004 40(1):6-9), acetaminophen-related liver failure appears to be on the rise. Researchers at the University of Washington Medical Center in Seattle found that between 1998 and 2003, the percentage of acute liver failure cases attributed to acetaminophen nearly doubled, rising from 28% to 51%. Acetaminophen toxicity may go beyond liver and may involve kidneys and/or myocardium (JT DiPiro, R L Talbert, G C Yee, G R Matzke, B G Wells, L M Posey (eds) Pharmacotherapy: A Physiological Approach 6th ed McGraw Hill (New York 2005) pp. 133). For extensive information collected by the US FDA for an Advisory Panel meeting on acetaminophen-related toxicity, see http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Drug SafetyandRiskManagementAdvisoryCommittee/UCM164897.pdf.
Acetaminophen induced hepatic toxicity has been found to be dependent on both acetaminophen blood level concentration and length of exposure. Previously, acetaminophen package labels instructed patients to not use the maximum dosage (4,000 mg per day) for more than 10 days, and to not take the product for pain for more than 10 days, or for fever for more than 3 days unless directed by a physician. Even healthy adults receiving 4,000 mg of acetaminophen per day for 14 days show elevated levels of enzymes indicative of liver toxicity (Journal Amer. Med. Assoc. 296, 87-93, 2006). In 2011 the US FDA announced that it is asking manufacturers of prescription acetaminophen combination products to limit the maximum amount of acetaminophen in these products to 325 mg per tablet, capsule, or other dosage unit. FDA believes that limiting the amount of acetaminophen per tablet, capsule, or other dosage unit in prescription products will reduce the risk of severe liver injury from acetaminophen overdosing, an adverse event that can lead to liver failure, liver transplant, and death. In response to these concerns, the pharmaceutical company Johnson and Johnson relabeled its products to recommend a maximum daily dose of no more than 3000 mg per day. Compounds that provide the therapeutic benefit of acetaminophen but which exhibit reduced hepatic toxicity would be particularly beneficial.
Acetaminophen's previous daily dose limit of 4 grams reduces its therapeutic utility, as 4 grams can be consumed in 16 hours (1 gram every 4 hours) leaving the remaining 8 hours of the day to seek alternative analgesics. Further, ethnic and intersubject variability in acetaminophen metabolism have been reported to be as high as 60-fold (S. Bridger, et al. BMJ 1998; 316:1724-1725), which complicates the acetaminophen safety profile as it imparts a high degree of uncertainty in the toxic dose for a given patient. By attenuating toxicity, improved compounds may provide greater utility by allowing doses higher than 4 grams and/or provide a larger safety margin for patients of any ethnic background. For use in patients with neuronal or myocardial injury, which takes advantage of acetaminophen's ability to protect tissues, the ability to administer high dose levels without fear of hepatoxicity would be particularly attractive to physicians. Hepatoprotectant acetaminophen mutual prodrugs have been described, e.g., in PCT Publication No. WO 2009/143299.
Parenteral formulations of acetaminophen (e.g., intravenous formulations) would be particularly useful in clinical settings. Compared to oral formulations, an acetaminophen parenteral dosage form, such as intravenous bolus or subcutaneous injection, would have various therapeutic advantages. For instance, parenteral acetaminophen may have relatively faster onset of action and ease of administration in settings such as post surgical recovery and trauma. Additionally, as acetaminophen has a relatively short half-life (about 2 hours; see Goodman and Gillman's The Pharmacological Basis of Therapeutics 10th ed, McGraw-Hill 2001, p 704), parenterally-administered acetaminophen may be provided at a lower dosage than oral acetaminophen, since much of the orally-administered acetaminophen is cleared from the body through conjugative first pass metabolism in the liver before reaching peak blood concentrations.
Despite a desire for an acetaminophen dosage form suitable for parenteral administration, development of effective therapeutic acetaminophen beyond oral dosage forms has been limited. A major barrier to developing a parenteral dosage form has been acetaminophen's low water solubility (about 1.3 g per 100 mL). To address acetaminophen's inherent solubility, U.S. Pat. No. 4,322,410 discloses, e.g., a water soluble phosphate derivative of acetaminophen (4-acetamidophenyl dihydrogen phosphate), which has a reported water solubility of 50 g per 100 mL of water. However, this acetaminophen derivative is reportedly not readily amenable to chemical and/or enzymatic hydrolysis (and thus not amenable to clinical use) as it requires alkaline phosphatase and about 15 hours in vitro to yield the desired acetaminophen drug from the derivative (see Chemical and Pharmaceutical Bulletin 29 (2): 577-580, 1981). Other phosphate-containing prodrugs have been disclosed in, for example, U.S. Pat. Nos. 4,322,410; 5,985,856; 6,204,257; 6,451,776; 6,872,838; and 7,244,718; U.S. patent application Ser. No. 11/999,660 (US2008/0318905), filed Dec. 5, 2007 and PCT Publication No. WO 2009/143295. Additional accetaminophen prodrugs have been described in U.S. Patent Application Publication No. 20110212926, U.S. Patent Application Publication No. 20110212927 and PCT Publication No. WO 2009/143299.
An injectable ester prodrug of acetaminophen with improved solubility profile, Propacetamol® (4-acetamidophenyl 2-(diethylamino)acetate) was developed in Europe and was later shown to have an inferior local tolerance profile when compared to acetaminophen (90% vs. 52%, British Journal of Anaesthesia 94 (5): 642-648, 2005; 49% vs. 0%, Anesthesia and Analgesia 101; 90-96, 2005). Another acetaminophen product marketed in Europe, Perfalgan®, is a large-volume (100-mL) formulation of acetaminophen for intravenous infusion over a relatively long period (about 15 minutes). These products are not optimal clinical solutions either because of their tolerance profile or administration requirements.
Thus, there is still a clear unmet need for improved acetaminophen type drugs, such as agents which exhibit enhanced water solubility and/or reduced hepatotoxicity as compared to acetaminophen. For use in patients with neuronal or myocardial injury, which takes advantage of acetaminophen's ability to protect tissues, the ability to rapidly and conveniently administer high dose levels would be particularly attractive to health care providers.
The disclosures of all publications, patents, patent applications and other references referred to herein are hereby incorporated herein by reference in their entireties.